Photofrin

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Photofrin

CLINICAL PHARMACOLOGY

Mechanism of Action

Cellular damage caused by photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) is a consequence
of the propagation of radical reactions. Radical initiation may occur after
porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer
from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent
radical reactions can form superoxide and hydroxyl radicals. Tumor death also
occurs through ischemic necrosis secondary to vascular occlusion that appears
to be partly mediated by thromboxane A2 release. As opposed to a thermal effect,
the laser treatment with porfimer sodium induces a photochemical effect. The
necrotic reaction and associated inflammatory responses may evolve over several
days.

Pharmacodynamics

The cytotoxic and antitumor actions of PHOTOFRIN (porfimer sodium) are light and oxygen dependent.
PDT with PHOTOFRIN (porfimer sodium) is a two-stage process. The first stage is the intravenous
injection of PHOTOFRIN (porfimer sodium) . Clearance from a variety of tissues occurs over 40-72
hours, but tumors, skin, and organs of the reticuloendothelial system (including
liver and spleen) retain PHOTOFRIN (porfimer sodium) for a longer period. Illumination with 630
nm wavelength laser light constitutes the second stage of therapy. Tumor selectivity
in treatment occurs through a combination of selective retention of PHOTOFRIN (porfimer sodium)
and selective delivery of light.

Pharmacokinetics

The pharmacokinetics of PHOTOFRIN (porfimer sodium) were studied in 18 cancer patients who received
two doses of PHOTOFRIN (porfimer sodium) , 2 mg/kg each, administered 30 to 45 days apart as slow
IV injection over 3 to 5 minutes. The mean Cmax values were comparable after
the first and second administrations (43.1±10.5 mcg/mL and 41.3±8.7
mcg/mL, respectively). However, the mean AUC0-inf of porfimer was about 34%
higher after the second administration than that after the first administration
(3937±1034 mcg.h/mL and 2937±627 mcg.hour/mL, respectively), indicating
some accumulation upon repeated administration. The elimination half-life of
porfimer increased from 410 to 725 hours after the first and second administrations,
respectively.

PHOTOFRIN (porfimer sodium) was approximately 90% protein bound in human serum, studied in
vitro . The binding was independent of concentration over the concentration
range of 20–100 mcg/mL.

Effect of Gender

The effect of gender was determined in 18 patients (8 males and 10 females)
who received two administrations of PHOTOFRIN (porfimer sodium) 2 mg/kg within 30-45 days apart
as slow IV injection over 3 to 5 minutes. The mean Cmax and AUC values were
comparable between males and females following either the first or the second
administrations.

Effect of Hepatic and Renal Impairment:

The effect of hepatic and renal impairment has not been studied.

Clinical Studies

Clinical studies of photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) were conducted
in patients with obstructing esophageal and endobronchial non-small-cell lung
cancers, in patients with early-stage radiologically occult endobronchial cancer,
and in patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE).
In all clinical studies, the method of PDT administration was essentially identical.
A course of therapy consisted of one injection of PHOTOFRIN (porfimer sodium) (2 mg/kg administered
as a slow intravenous injection over 3–5 minutes) followed by up to two non-thermal
applications of 630 nm laser light. Light doses of 300 J/cm of diffuser length
were used in esophageal cancer. Light doses of 200 J/cm of diffuser length were
used in endobronchial cancer for both palliation of obstructing cancer and treatment
of superficial lesions. For the ablation of HGD in BE, the light dose administered
was 130 J/cm of diffuser length using a centering balloon for the first application
and 50 J/cm of diffuser length without a centering balloon for the second application
[see DOSAGE AND ADMINISTRATION]. In all cases, the first application
of light occurred 40–50 hours after PHOTOFRIN (porfimer sodium) injection.

For treatment of esophageal cancer debridement of residua via endoscopy is
optional 96–120 hours after injection, after which any residual tumor could
be retreated with a second laser light application at the same light dose used
for the initial treatment. Additional courses of PDT with PHOTOFRIN (porfimer sodium) were allowed
after one month, up to a maximum of three courses.

For treatment of endobronchial cancer, debridement of residua was performed
via bronchoscopy 96–120 hours after injection, after which any residual tumor
could be retreated with a second laser light application at the same light dose
used for the initial treatment. Additional courses of PDT with PHOTOFRIN (porfimer sodium) were
allowed after one month, up to a maximum of three courses.

For ablation of HGD in BE, a second laser light application of 50 J/cm of diffuser
length without a centering balloon could be given 96-120 hours after the PHOTOFRIN (porfimer sodium)
injection for untreated areas (“skip” areas). Additional courses
of PDT with PHOTOFRIN (porfimer sodium) were allowed after three months, up to a maximum of three
courses.

Esophageal Cancer

PDT with PHOTOFRIN (porfimer sodium) was utilized in a multicenter, single-arm study in 17 patients
with completely obstructing esophageal carcinoma. Assessments were made at 1
week and 1 month after the last treatment procedure. As shown in Table 10, after
a single course of therapy, 94% of patients obtained an objective tumor response
and 76% of patients experienced some palliation of their dysphagia. On average,
before treatment these patients had difficulty swallowing liquids, even saliva.
After one course of therapy, there was a statistically significant improvement
in mean dysphagia grade (1.5 units, p < 0.05) and 13 of 17 patients could
swallow liquids without difficulty 1 week and/or 1 month after treatment. Based
on all courses, three patients achieved a complete tumor response (CR). In two
of these patients, the CR was documented only at Week 1 as they had no further
assessments. The third patient achieved a CR after a second course of therapy,
which was supported by negative histopathology and maintained for the entire
follow-up of 6 months.

Of the 17 treated patients, 11 (65%) received clinically important benefit
from PDT. Clinically important benefit was defined hierarchically as a complete
tumor response (3 patients), achievement of normal swallowing (2 patients went
from Grade 5 dysphagia to Grade 1), or achievement of a marked improvement of
two or more grades of dysphagia with minimal adverse reactions (6 patients).
The median duration of benefit in these patients was 69 days. Duration of benefit
was calculated only for the period with documented evidence of improvement.
All of these patients were still in response at their last assessment and, therefore,
the estimate of 69 days is conservative. The median survival for these 11 patients
was 115 days.

Endobronchial Cancer

Two randomized multicenter Phase III studies were conducted to compare the
safety and efficacy of PHOTOFRIN (porfimer sodium) PDT versus Nd:YAG laser therapy for reduction
of obstruction and palliation of symptomatic patients with partially or completely
obstructing endobronchial non-small-cell lung cancer. Assessments were made
at 1 week and at monthly intervals after treatment. Table 11 shows the results
from all randomized patients in the two studies combined. Objective tumor response
rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT
and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60%
for PDT and 41% for Nd:YAG.

Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity
rating scale for dyspnoea, cough, and hemoptysis. Patients with moderate to
severe symptoms are those most in need of palliation. Improvements of 2 or more
grades are considered to be clinically significant. Table 12 shows the percentages
of patients with moderate to severe symptoms at baseline who demonstrated a
2grade improvement at any time during the interval evaluated.

a Statistical comparisons were
precluded by the amount of missing data at Month 1 or later (e.g., for
tumor response, PDT 28% missing, Nd:YAG 38%). b CR+PR where CR = complete response (absence of bronchoscopically
visible tumor) and PR = partial response (increase of ≥ 50% in the smallest
luminal diameter; or any appearance of a lumen for completely obstructing
tumors). c In patients with atelectasis at baseline.

a Statistical comparisons were
precluded by the amount of missing data at Month 1 or later. b Dyspnoea was graded on a 6-point severity rating scale; cough
and hemoptysis on a 5-point scale. Clinically significant improvement
was defined as a change of at least two grades from baseline.

In a separate retrospective analysis, patients were individually evaluated
to identify those patients whose benefit to risk ratio was most favorable, i.e.,
those who obtained clinically important benefit with minimal adverse reactions.
Clinically important benefit was defined as one of the following:

Thirty-six (36) of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated
patients (23%) received clinically important benefit with only minimal or moderate
toxicities of short duration. Thirty-four (34) of 99 PDT-treated patients demonstrated
improvements in 2 or more efficacy endpoints (dyspnoea, cough, hemoptysis, sputum,
atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Performance
Score or tumor response) and 29 patients had improvements in 3 or more.

The median duration of documented benefit in the 36 patients was 63 days. In
these patients with late-stage obstructing lung cancer, median survival was
174 days in PDT-treated patients and 161 days in Nd:YAG-treated patients.

The efficacy of PHOTOFRIN (porfimer sodium) PDT was also evaluated in the treatment of microinvasive
endobronchial tumors in 62 inoperable patients in three noncomparative studies.
Microinvasive lung cancer is defined histologically as disease, which invades
beyond the basement membrane but not through or into the cartilage. For 11 of
the 62 patients, it was clearly documented that surgery and radiotherapy were
not indicated. These 11 patients were all inoperable for medical or technical
reasons. Radiotherapy was not indicated due to prior high-dose radiotherapy
(7 patients), poor pulmonary function (2 patients), multifocal multilobar disease
(1 patient), and poor medical condition (1 patient). As shown in Table 13, the
complete tumor response rate, biopsy-proven at least 3 months after treatment,
was 50%, median time to tumor recurrence was more than 2.7 years, median survival
was 2.9 years and disease-specific survival was 4.1 years.

a Not included are an additional
18 patients (6 patients not eligible for surgery or radiotherapy) who
had complete tumor responses which were documented earlier than 3 months
after treatment. b The upper limit of the confidence interval could not be estimated
due to an insufficient number of patients whose tumors recurred (Time
to Tumor Recurrence) or who died (Survival).

High-Grade Dysplasia in Barrett's Esophagus

The safety and efficacy of PDT with PHOTOFRIN (porfimer sodium) in ablation of HGD in patients
with BE was assessed in one controlled randomized clinical study and two supportive
studies.

Controlled Randomized Study

A multicenter, pathology blinded, randomized, controlled study was conducted
in North America and Europe to assess the efficacy of PDT with PHOTOFRIN (porfimer sodium) for
Injection plus omeprazole (PHOTOFRIN (porfimer sodium) PDT + OM) in producing complete ablation
of HGD in patients with BE compared to control patients receiving omeprazole
alone (OM Only). A total of 485 patients with the diagnosis of HGD were screened
for the study; 208 (43%) were randomized to treatment, 237 (49%) were excluded
because the diagnosis of HGD was not confirmed and 40 (8%) did not meet other
screening criteria or declined to participate in the study. The high patient
exclusion rate re-enforces the recommendation by the American College of Gastroenterology
that the diagnosis of HGD in BE should be confirmed by an expert GI pathologist.
Patients were centrally randomized in a 2:1 proportion to receive PHOTOFRIN (porfimer sodium)
PDT + OM (138 patients) or OM Only (70 patients). All patients underwent rigorous
systematic quarterly endoscopic biopsy surveillance. Four-quadrant jumbo biopsies
at every 2 cm of the entire Barrett's mucosa were obtained at each follow-up
visit (every three months or six months if four consecutive quarterly follow-up
endoscopic biopsy results were negative for HGD). All histological assessments
were carried out at a central pathology laboratory and read by pathologists
blinded to the treatment administered.

A total of 208 patients who had biopsy-proven HGD in BE were enrolled in the
initial 2-year phase of the study. Of those, 199 patients were considered evaluable:
130 of 138 (94%) patients randomized to the PHOTOFRIN (porfimer sodium) PDT + OM group and 69
of 70 (99%) randomized to the OM Only group had no esophageal invasive cancer,
suspicion of esophageal invasive cancer, lymph node involvement, or metastases,
and had received at least one PHOTOFRIN (porfimer sodium) PDT course or one week of OM treatment,
respectively. A disproportionate percentage of patients were discontinued from
the OM Only group during the initial 2-year phase leaving 81 (59%) patients
in the PHOTOFRIN (porfimer sodium) PDT + OM group and 21 (30%) patients in the OM Only group at
the end of the 2-year phase. Consequently, a total of 102 patients who completed
the initial 2-year phase were eligible for continuation into the long-term phase
until completion of 5 years; of those, 48 (59%) patients from the PHOTOFRIN (porfimer sodium)
PDT + OM group and 13 (62%) patients from the OM Only group consented to pursue
the long-term phase until completion of 5 years. The mean age was 66 years (38
to 89 years) in the PHOTOFRIN (porfimer sodium) PDT + OM group, and 67 (36 to 88 years) in the
OM Only group. The patients in both treatment groups were predominantly male
(85%), Caucasian (99%), and former smokers (64%). These characteristics are
typical of patients with HGD in BE. Patients randomized to the PHOTOFRIN (porfimer sodium) PDT
+ OM treatment received up to three courses of treatment separated by at least
90 days. Each course consisted of intravenous administration of 2.0 mg/kg of
PHOTOFRIN (porfimer sodium) followed 40-50 hours later by a 630 nm laser light dose of 130 J/cm
of diffuser length delivered using a centering balloon. A second laser light
dose of 50 J/cm of diffuser length could be administered without a centering
balloon 96-120 hours after the injection of PHOTOFRIN (porfimer sodium) for treatment of “skip”
areas. Since centering balloons are up to 7 cm in length, patients with more
extensive HGD were treated with two or three courses. Both the PHOTOFRIN (porfimer sodium) PDT
treatment group and the control group received 20 mg of omeprazole BID to decrease
reflux esophagitis. The mean duration of the follow-up period was 34 months
(0-67 months) for the PHOTOFRIN (porfimer sodium) PDT + OM group and 25 months (0-65 months) for
the OM Only group.

The primary efficacy endpoint was the Complete Response rate (CR3 or better)
at any one of the endoscopic assessment time points. The CR3 or better response
was defined as the complete ablation of HGD and referred to as a composite of
the following three response levels.

CR2 – Ablation of all histological grades of dysplasia, including patients
with indefinite grade of dysplasia, but some areas of Barrett's epithelium
still remain; and

CR3 – Ablation of all areas of HGD but with some areas of low-grade dysplasia
with or without areas which are indefinite for dysplasia, or areas of Barrett's
metaplastic epithelium.

Additional efficacy endpoints included:

Quality of Complete Response, which consisted of CR1 and CR2 or better.

Duration of CR;

Time to Progression to Cancer.

Table 14 presents the overall clinical response for both treatment groups in
the intent-to-treat (ITT) population whose response was CR3 or better at any
one of the evaluation time points. Overall, PHOTOFRIN (porfimer sodium) PDT + OM was effective
in eliminating HGD in patients with BE. The proportion of responders was significantly
higher in the PHOTOFRIN (porfimer sodium) PDT + OM group than in the OM Only group (77% vs. 39%,
respectively; p < 0.0001).

The quality of response in the PHOTOFRIN (porfimer sodium) PDT + OM group was significantly better
than that measured in the OM Only group at all response levels (p < 0.0001).
Seventy-two (52%) patients in the PHOTOFRIN (porfimer sodium) PDT + OM group achieved a CR1 response
as compared to only five (7%) patients in the OM Only group. Eighty-one (59%)
patients in the PHOTOFRIN (porfimer sodium) PDT + OM group achieved a CR2 or better response as
compared to ten (14%) patients in the OM Only group.

TABLE 14: Complete Response Rates After a Minimum Follow-Up
of 24 Months in the ITT Population

Responders

Treatment Groups

PHOTOFRIN PDT + OM

OM Only

p-valuea

Numbers of patients

N

138

70

CR3 or betterb

n

106

27

Proportion

(%)

0.768 (76.8)

0.386 (38.6)

< 0.0001

95% CI

(0.689, 0.836)

(0.272, 0.510)

a Fisher's Exact test.b CR3 or better: Ablation of all areas of HGD.
NOTE: Six patients in the PHOTOFRIN (porfimer sodium) PDT + OM group and three patients
in the OM Only group without post-baseline biopsy data are considered
as non-responders.

At the end of the long-term phase, the median response duration was 44.6 months
(95% CI: 15.0-not reached, months) in the PHOTOFRIN (porfimer sodium) PDT + OM group compared
to 3.2 months (95% CI: 3.03.4, months) in the OM Only group.

At the end of the initial 2 year phase, the time to progression to cancer was
significantly longer in the PHOTOFRIN (porfimer sodium) PDT + OM group compared to the OM Only
group (HR=0.36 (95% CI: 0.19-0.69), a hazard ratio less than 1 favors the PHOTOFRIN (porfimer sodium)
PDT + OM group). The proportion of patients' progression to cancer was lower
in the PHOTOFRIN (porfimer sodium) PDT + OM group than in the OM Only group: 13% (18 of 138 patients)
vs. 28% (20 of 70 patients).

Supportive Studies

Two uncontrolled, supportive studies were conducted that were physician-sponsored,
single center Phase II trials. Both studies included patients that had low-grade
dysplasia (LGD), HGD and early adenocarcinoma. All HGD in BE patients were treated
with PHOTOFRIN (porfimer sodium) PDT and omeprazole.

The first study enrolled 99 patients (44 with HGD); the purpose of this study
was to determine the required light dose to produce effective results. The second
study enrolled 86 patients (42 with HGD), who were randomized to receive either
PHOTOFRIN (porfimer sodium) PDT with prednisone or PHOTOFRIN (porfimer sodium) PDT without prednisone to determine
whether steroid treatment would reduce the incidence and severity of esophageal
strictures.

A CR3 or better response was demonstrated in 93% of 44 patients with HGD in
the first study and in 95% of 42 patients with HGD in the second study after
a minimum follow-up of 12 months. A CR2 or better response was achieved in 82%
of patients in the first study and in 91% of patients in the second study. A
CR1 response occurred in 57% of patients in the first study and in 60% of the
second study. Progression to cancer during the above follow-up period occurred
in 18% of patients in the first study and in 7% of patients in the second study.
No reduction in the incidence or severity of esophageal strictures was found
in the prednisone group in the second study.

Last reviewed on RxList: 5/19/2011
This monograph has been modified to include the generic and brand name in many instances.